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Tranexamic acid in pediatric hemorrhagic trauma
Borgman, M. A., Nishijima, D. K.
The Journal of Trauma and Acute Care Surgery. 2023;94(1S Suppl 1):S36-s40
Abstract
There is strong evidence in adult literature that tranexamic acid (TXA) given within 3 hours from injury is associated with improved outcomes. The evidence for TXA use in injured children is limited to retrospective studies and one prospective observational trial. Two studies in combat settings and one prospective civilian US study have found association with improved mortality. These studies indicate the need for a randomized controlled trial to evaluate the efficacy of TXA in injured children and to clarify appropriate timing, dose and patient selection. Additional research is also necessary to evaluate trauma-induced coagulopathy in children. Recent studies have identified three distinct fibrinolytic phenotypes following trauma (hyperfibrinolysis, physiologic fibrinolysis, and fibrinolytic shutdown), which can be identified with viscohemostatic assays. Whether viscohemostatic assays can appropriately identify children who may benefit or be harmed by TXA is also unknown.
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Effectiveness and safety of tranexamic acid in pediatric trauma: A systematic review and meta-analysis
Kornelsen, E., Kuppermann, N., Nishijima, D. K., Ren, L. Y., Rumantir, M., Gill, P. J., Finkelstein, Y.
The American Journal of Emergency Medicine. 2022;55:103-110
Abstract
OBJECTIVE Trauma is the leading cause of childhood death in the United States. Our goal was to determine the effectiveness of tranexamic acid (TXA) in improving survival in pediatric trauma. METHODS MEDLINE (OVID), Embase (OVID), Cochrane Central Register databases, CINAHL (EBSCO), Web of Science (Clarivate Analytics), and grey literature sources were searched for publications reporting survival and safety outcomes in children receiving TXA in acute trauma, with no language restrictions, published until February 11, 2021. Two independent researchers assessed studies for eligibility, bias, and quality. Data on the study setting, injury type, participants, design, interventions, TXA dosing and outcomes were extracted. The primary outcome was survival in children who received TXA following trauma. Forest plots of effect estimates were constructed for each study. Heterogeneity was assessed and data were pooled by meta-analysis using a random-effects model. RESULTS Fourteen articles met inclusion criteria - six single-institution and eight multicentre retrospective cohort studies. Overall, TXA use was not associated with increased survival in pediatric trauma (adjusted odds ratio [aOR]: 0.61, 95% CI: 0.30-1.22) after adjustment for patient-level variables, such as injury severity. Increased survival was documented in the subset of children experiencing trauma in combat settings (aOR for mortality: 0.31, 95% CI: 0.14-0.68). There were no differences in the odds of thromboembolic events (OR 1.15, 95% CI: 0.46-2.87) in children who received TXA versus not. CONCLUSIONS The utility of TXA in children with trauma is unclear. Guidelines supporting TXA use in pediatric trauma may not be based on the available evidence of its use in this context. Rigorous trials measuring survival and other meaningful outcomes and exploring optimal TXA dosing are urgently needed. Study Registration (PROSPERO): CRD42020157683.
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Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): a pilot randomized trial
Nishijima DK, VanBuren JM, Linakis SW, Hewes HA, Myers SR, Bobinski M, Tran NK, Ghetti S, Adelson PD, Roberts I, et al
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2022
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Editor's Choice
Abstract
BACKGROUND The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries. METHODS Severely injured children (0 up to 18(th) birthday) were randomized into a double-blind randomized trial of 1) TXA 15 mg/kg bolus dose, followed by 2 mg/kg/hr infusion over 8 hours, 2) TXA 30 mg/kg bolus dose, followed by 4 mg/kg/hr infusion over 8 hours, or 3) normal saline placebo bolus and infusion. The trial was conducted at 4 pediatric Level I trauma centers in the United States between June 2018 and March 2020. We enrolled patients under federal exception from informed consent (EFIC) procedures when parents were unable to provide informed consent. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The target enrollment rate was at least 1.25 patients per site per month. RESULTS A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified. CONCLUSION Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.
PICO Summary
Population
Severely injured children enrolled in the TIC-TOC trial across four centers in US (n= 31).
Intervention
15 mg/kg of tranexamic acid (TXA) dose, followed by 2 mg/kg/hr infusion (n= 9).
Comparison
30 mg/kg of TXA dose, followed by 4 mg/kg/hr infusion (n= 10). Saline placebo and infusion (n= 12).
Outcome
All patients had their primary outcome measured. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. No statistically significant differences in any of the clinical outcomes were identified.
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Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial
Crombie N, Doughty HA, Bishop JRB, Desai A, Dixon EF, Hancox JM, Herbert MJ, Leech C, Lewis SJ, Nash MR, et al
The Lancet. Haematology. 2022
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Editor's Choice
Abstract
BACKGROUND Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING National Institute for Health Research Efficacy and Mechanism Evaluation.
PICO Summary
Population
Patients aged 16 years old or older with trauma-related haemorrhagic shock enrolled in the resuscitation with pre-hospital blood products (RePHILL) trial, based across four UK prehospital critical care services (n= 432).
Intervention
Packed red blood cells and lyophilised plasma (PRBC-LyoPlas, n= 209).
Comparison
Sodium chloride (n= 223).
Outcome
The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. The composite primary outcome occurred in 128 (64%) of 199 patients receiving PRBC-LyoPlas and 136 (65%) of 210 receiving sodium chloride. The rates of transfusion-related complications in the first 24 hours after emergency department arrival were similar (PRBC-LyoPlas eleven (7%) of 148 compared with sodium chloride nine (7%) of 137). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in the sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the sodium chloride group (abnormal liver function test). There were no treatment-related deaths.
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Metrics of shock in pediatric trauma patients: A systematic search and review
Alberto, E. C., McKenna, E., Amberson, M. J., Tashiro, J., Donnelly, K., Thenappan, A. A., Tempel, P. E., Ranganna, A. S., Keller, S., Marsic, I., et al
Injury. 2021;52(10):3166-3172
Abstract
INTRODUCTION Shock-index (SI) and systolic blood pressure (SBP) are metrics for identifying children and adults with hemodynamic instability following injury. The purpose of this systematic review was to assess the quality of these metrics as predictors of outcomes following pediatric injury. MATERIALS AND METHODS We conducted a literature search in Pubmed, SCOPUS, and CINAHL to identify studies describing the association between shock metrics on the morbidity and mortality of injured children and adolescents. We used the data presented in the studies to calculate the sensitivity and specificity for each metric. This study was registered with Prospero, protocol CRD42020162971. RESULTS Fifteen articles met the inclusion criteria. seven studies evaluated SI or SIPA score, an age-corrected version of SI, as predictors of outcomes following pediatric trauma, with one study comparing SIPA score and SBP and one study comparing SI and SBP. The remaining eight studies evaluated SBP as the primary indicator of shock. The median sensitivity for predicting mortality and need for blood transfusion was highest for SI, followed by SIPA, and then SBP. The median specificity for predicting these outcomes was highest for SBP, followed by SIPA, and then SI. CONCLUSIONS Common conclusions were that high SIPA scores were more specific than SI and more sensitive than SBP. SIPA score had better discrimination for severely injured children compared to SI and SBP. An elevated SIPA was associated with a greater need for blood transfusion and higher in-hospital mortality. SIPA is specific enough to exclude most patients who do not require a blood transfusion.
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Enrollment with and without Exception from Informed Consent in a Pilot Trial of Tranexamic Acid in Children with Hemorrhagic Injuries
Linakis SW, Kuppermann N, Stanley RM, Hewes H, Myers S, VanBuren JM, Charles Casper T, Bobinski M, Ghetti S, Schalick WO 3rd, et al
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2021
Abstract
BACKGROUND Federal exception from informed consent (EFIC) procedures allow studies to enroll patients with time-sensitive, life-threatening conditions when written consent is not feasible. Our objective was to compare enrollment rates with and without EFIC in a trial of tranexamic acid (TXA) for children with hemorrhagic injuries. METHODS We conducted a four-center randomized controlled pilot and feasibility trial evaluating TXA in children with severe hemorrhagic brain and/or torso injuries. We initiated the trial enrolling patients without EFIC. After 3 months of enrollment, we met our a priori futility threshold and paused the trial to incorporate EFIC procedures and obtain regulatory approval. We then restarted the trial allowing EFIC if the guardian was unable to provide timely written consent. We used descriptive statistics to compare characteristics of eligible patients approached with and without EFIC procedures. We also calculated the time delay to restart the trial using EFIC. RESULTS We enrolled 1 of 15 (6.7%) eligible patients (0.17 per site per month) prior to using EFIC procedures. Of the 14 missed eligible patients, 7 (50%) were not enrolled because guardians were not present or were injured and unable to provide written consent. After obtaining approval for EFIC, we enrolled 30 of 48 (62.5%) eligible patients (1.34 per site per month). Of these 30 patients, 22 (73.3%) were enrolled with EFIC. Of the 22, no guardians refused written consent after randomization. There were no significant differences in the eligibility rate and patient characteristics enrolled with and without EFIC procedures. Across all sites, the mean delay to restart the trial using EFIC procedures was 12 months. CONCLUSIONS In a multicenter trial of severely injured children, the use of EFIC procedures greatly increased the enrollment rate and was well accepted by guardians. Initiating the trial without EFIC procedures led to a significant delay in enrollment.
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Appropriate Tourniquet Types in the Pediatric Population: A Systematic Review
Charlton NP, Goolsby CA, Zideman DA, Maconochie IK, Morley PT, Singletary EM
Cureus. 2021;13(4):e14474
Abstract
Trauma is the leading cause of mortality in those aged 1-19, with hemorrhage accounting for up to 40% of all trauma deaths. Manufactured tourniquets are recommended for the control of life-threatening extremity hemorrhage in adults but their use in the pediatric population requires further investigation. We performed a systematic review to evaluate the most appropriate tourniquet design for use in the pediatric population. A literature search of Embase and the Cochran databases of trials and systematic reviews on October 1, 2020 identified 454 unique references, of which 15 were included for full-text screening. Two single-arm observational studies with a high risk of bias evaluated the use of windlass tourniquets in the pediatric population (73 patients, age 2-16 years). The certainty of the evidence was very low. In both studies, conducted on uninjured extremities, the use of a manufactured windlass tourniquet, specifically the Combat Application Tourniquet (C-A-T®) Generation 7, led to the cessation of Doppler detected pulses in 71/71 (100%) of upper extremities and 69/73 (94.5%) of lower extremities. Of the four failures, one participant withdrew due to pain and three tourniquet applications failed to occlude pulses after three turns of the windlass. No controls were used for comparison. In conclusion, two observational studies demonstrated that windlass tourniquets were able to abolish distal pulses in children as young as two years of age and with a minimum limb circumference of 13 cm. These preliminary findings may be helpful for organizations in the creation of guidelines for the management of life-threatening extremity bleeding in children.
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Outcome measures used in clinical research evaluating pre-hospital blood component transfusion in traumatically injured bleeding patients: A systematic review
Tucker H, Avery P, Brohi K, Davenport R, Griggs J, Weaver A, Green L
The journal of trauma and acute care surgery. 2021
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Editor's Choice
Abstract
BACKGROUND Trial outcomes should be relevant to all stakeholders, and allow assessment of interventions' efficacy and safety at appropriate timeframes. There is no consensus regarding outcome measures in the growing field of pre-hospital trauma transfusion research. Harmonization of future clinical outcome reporting is key to facilitate inter-study comparisons and generate cohesive, robust evidence to guide practice. OBJECTIVES To evaluate outcome measures reported in pre-hospital trauma transfusion trials. METHODS Data Sources, Eligibility Criteria, Participants and InterventionsWe conducted a scoping systematic review to identify the type, number and definitions of outcomes reported in randomised controlled trials, prospective and retrospective observational cohort studies investigating pre-hospital blood component transfusion in adult and paediatric patients with traumatic haemorrhage. Electronic database searching of PubMed, Embase, Web of Science, Cochrane, OVID, clinical trials.gov, and the Transfusion Evidence Library was completed in accordance with PRISMA guidelines.Study Appraisal and Synthesis MethodsTwo review authors independently extracted outcome data. Unique lists of salutogenic (patient-reported health and wellbeing outcomes) and non-salutogenic focused outcomes were established. RESULTS 3,471 records were identified. 34 studies fulfilled inclusion criteria: four military (n = 1,566 patients) and 30 civilian (n = 14,398 patients), all between 2000 and 2020. 212 individual non-patient-reported outcomes were identified, which collapsed into 20 outcome domains with varied definitions and timings. All primary outcomes measured effectiveness, rather than safety or complications. 69% reported mortality, with 11 different definitions. No salutogenic outcomes were reported. LIMITATIONS The review is limited by a lack of high-grade prospective comparative trials with clear predefined primary outcomes. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS There is heterogeneity in outcome reporting and definitions, an absence of patient-reported outcome, and an emphasis on clinical effectiveness rather than safety or adverse events in pre-hospital trauma transfusion trials. We recommend stakeholder consultation and a Delphi process to develop a clearly defined minimum core outcome set for pre-hospital trauma transfusion trials. SYSTEMATIC REVIEW REGISTRATION NUMBER This review was prospectively registered with PROSPERO (CRD42019131406). LEVEL OF EVIDENCE II. STUDY TYPE Scoping Systematic Review.
PICO Summary
Population
Adult and paediatric patients with traumatic haemorrhage (34 studies, n= 15,964).
Intervention
Systematic review to identify the type, number and definitions of outcomes reported in pre-hospital trauma transfusion research.
Comparison
Outcome
212 individual non-patient-reported outcomes were identified, which collapsed into 20 outcome domains with varied definitions and timings. All primary outcomes measured effectiveness, rather than safety or complications. 69% reported mortality, with 11 different definitions. No salutogenic outcomes were reported.
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Accuracy of risk tools to predict critical bleeding in major trauma: a systematic review with meta-analysis
Gianola S, Castellini G, Biffi A, Porcu G, Napoletano A, Coclite D, D'Angelo D, Fauci AJ, Iacorossi L, Latina R, et al
The journal of trauma and acute care surgery. 2021
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Editor's Choice
Abstract
BACKGROUND Early detection of critical bleeding by accurate tools can help ensure rapid delivery of blood products to improve outcomes in major trauma patients. We conducted a systematic review to evaluate the accuracy of risk tools to predict critical bleeding in patients with major trauma. METHODS PubMed, Embase and CENTRAL were searched up to February 2021 for studies investigating risk tools to predict critical bleeding for major trauma people in pre-hospital and emergency department. We followed the PRISMA-DTA guidelines. Two independent authors included studies, extracted data, appraised the quality using the Quality Assessment of Diagnostic Accuracy Studies-2 and assessed the certainty of evidence using thee Grading of Recommendations Assessment, Development and Evaluation methodology. Sensitivity, specificity and the Receiver Operating Characteristics curve for all selected triage tools. RESULTS Eighty-nine observational studies for adults and 12 observational studies for children met our inclusion criteria. In adults, we found 23 externally validated and 28 un-validated tools; in children, 3 externally validated tools and 5 un-validated. In the externally validated tools, we identified those including clinical, laboratory and ultrasound assessments. Among tools including only a clinical assessment, the Shock Index showed high sensitivity and specificity with the Certainty of Evidence ranging from very low to moderate in adults, as well as Shock Index Pediatric Age-adjusted (SIPA) with a moderate Certainty of Evidence. We found that tools using clinical, laboratory and ultrasound assessments were overall more accurate than those tools without all three components. CONCLUSIONS Clinicians should consider risk tools to predict critical bleeding in a time-sensitive setting like major life threatening trauma. The Shock index and SIPA are easy and handy tools to predict critical bleeding in the pre-hospital setting. In the emergency department, however, many other tools can be utilized which include laboratory and ultrasound assessments, depending on staff experience and resources. LEVEL OF EVIDENCE Systematic review, diagnostic Level III.
PICO Summary
Population
Adults and children with major trauma (101 studies).
Intervention
Systematic review to identify the most accurate risk tools to predict critical bleeding.
Comparison
Outcome
Twenty-three externally validated and 28 un-validated tools were found for adults, and 3 externally validated tools and 5 un-validated, for children. Among tools including only a clinical assessment, the Shock Index showed high sensitivity and specificity with the Certainty of Evidence ranging from very low to moderate in adults, as well as Shock Index Paediatric Age-adjusted with a moderate Certainty of Evidence. It was found that tools using clinical, laboratory and ultrasound assessments were overall more accurate than those tools without all three components.
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Massive Transfusion Protocols in Pediatric Trauma Population: A Systematic Review
Kinslow K, McKenney M, Boneva D, Elkbuli A
Transfus Med. 2020
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Editor's Choice
Abstract
BACKGROUND Our main objective was to review the literature to answer the following questions regarding pediatric massive transfusion (PMT) protocols: 1) How is PMT defined? 2) Which blood product ratios have been investigated and what is their effect on outcomes? 3) What evidence exists regarding PMT outcomes? METHODS The PRISMA guidelines were used. We searched PubMed, Google Scholar, Cochrane Library, EMBASE, Wiley Online Library, and Ovid. Articles were screened for inclusion based on relevance to PMT. Articles were assessed for study design, presence of established/tested PMT, PMT definition, PMT activation criteria, and Transfusion Ratios, for final determination of article inclusion. RESULTS Our search produced 3213 articles with 33 included for final review. Existing definitions of PMT are based on volume administered/kg but vary in timeframe criteria (over 4 hr vs 24 hr). Some studies have investigated "high" balanced transfusion ratios as seen in adults (1:1 FFP:pRBC) with a few showing statistically significant improvement in pediatric mortality vs lower ratios. PMT protocol implementation has not been shown to consistently reduce pediatric trauma mortality across multiple centers. However, other operational aspects such as reduced time to first transfusion are apparent benefits. CONCLUSIONS There is poor consensus over the definition of PMT. Definitions that involve early recognition have the most promise for practice and future studies. Evidence supporting an optimal blood product ratio in PMT is also lacking but trends towards supporting balanced approaches. Implementation of PMT protocols have been limited in showing significant improvement of overall pediatric trauma mortality but may reduce associated morbidity.
PICO Summary
Population
Paediatric trauma patients undergoing massive transfusions (33 studies).
Intervention
Systematic review to define paediatric massive transfusion (PMT) protocols, and to review the evidence on PMT outcomes.
Comparison
Outcome
Existing definitions of PMT are based on volume administered/kg but vary in timeframe criteria (over 4 hr vs. 24 hr). Some studies have investigated "high" balanced transfusion ratios as seen in adults (1:1 FFP:pRBC) with a few showing statistically significant improvement in paediatric mortality vs. lower ratios. PMT protocol implementation has not been shown to consistently reduce paediatric trauma mortality across multiple centers. However, other operational aspects such as reduced time to first transfusion are apparent benefits.